Improving the Kinetics and Reliability of Continuous Glucose Monitoring

描述（由申请人提供）：当工程人工胰腺的目标最终实现时，1型糖尿病（T1DM）患者的生活质量和预期寿命将得到显著改善。这种系统的一个关键组成部分是能够快速、准确和连续地测量血糖的变化。植入式连续血糖监测仪是对几十年来一直是标准的手指测量的改进，但其性能受到目前植入式间质（皮下）空间的基本限制：1)血糖变化与间质葡萄糖变化之间存在较大的滞后时间；2)由于间质空间灌注的变化，滞后时间存在较大的变异性；3)由于间质氧张力的正常波动，存在稳态不准确性；4)由于组织包封，间质传感器需要频繁更换。这些限制阻碍了间质传感器在涉及血糖快速变化的日常活动（如饮食和运动）中实现严格的血糖控制。实现严格的血糖控制是我们研究项目的长期目标，因为它对预防T1DM患者的破坏性长期后遗症至关重要。本应用的目的是确定使用腹膜间隙（而不是间质间隙）进行葡萄糖传感的程度将使我们实现这一目标。我们的中心假设是，腹膜间隙中的液体跟踪血糖变化的滞后时间和滞后变变性比间隙小，因为血液流向这个中心，受保护的空间是丰富的，对温度和心输出量的变化是稳定的，因为腹膜间隙的葡萄糖动力学是快速的。此外，我们假设腹膜传感器与放置在间隙的相同传感器相比，会表现出较少的传感器间变异性和氧张力相关的不准确性。我们的假设得到了生理学文献和我们使用血糖挑战的初步研究的支持，这些研究显示腹膜间隙比间质传感器的葡萄糖反应更快。我们将通过比较植入腹膜和间质间隙的传感器的连续葡萄糖读数来验证这些假设，同时让实验动物（猪）进行静脉葡萄糖耐量试验。这些测试将在基线条件下进行，然后在体温和血压变化时再次进行，以测试稳健性。我们将测量所有情况下的滞后时间和滞后变异性。此外，我们将测试防止组织封装的专有技术，这是长期植入传感器面临的主要挑战之一。

DESCRIPTION (provided by applicant): Patients with type 1 diabetes mellitus (T1DM) will experience dramatic improvements in their quality of life and life expectancy when the goal of engineering an artificial pancreas is finally realized. A critical component of such a system is to be able to measure changes in blood glucose rapidly, accurately, and continuously. Implantable continuous glucose monitors are an improvement over the fingerstick measurements that have been the norm for decades, but their performance is hampered by fundamental limitations of the interstitial (subcutaneous) space where they are currently implanted: 1) there is substantial lag time between changes in blood glucose and changes in interstitial glucose, 2) there is substantial variability in the lag time because perfusion of the interstitial space is variable, 3) there are steady-state inaccuracies due normal fluctuations in interstitial oxygen tension, and 4) due to tissue encapsulation, interstitial sensors need to be replaced frequently. These limitations prevent interstitial sensors from being used to achieve tight glycemic control around routine activities that involve rapid changes in blood glucose, such as eating and exercise. Achieving tight glycemic control is the long-term goal of our research program, as it is critical to preventing the devastating long-term sequelae in patients with T1DM. The objective of this application is to determine the extent to which using the peritoneal space for glucose sensing (instead of the interstitial space) will move us toward this goal. Our central hypothesis is that the fluid in the peritoneal space tracks blood glucose changes with less lag time and less lag-time variability than the interstitial space, because the blood flow to this central, protected space is copious and robust to changes in temperature and cardiac output, and because the glucose kinetics of the peritoneal space are known to be fast. We additionally hypothesize that peritoneal sensors will exhibit less intersensor variability and oxygen- tension-related inaccuracies than the same sensors placed interstitially. Our hypothesis is supported by the physiology literature and by our pilot studies using a glycemic challenge, which show a faster glucose response for the peritoneal space vs. interstitial sensors. We will test these hypotheses by comparing continuous glucose readings from sensors implanted in the peritoneal vs. interstitial spaces while exposing experimental animals (pigs) to intravenous glucose tolerance tests. These tests will be done under baseline conditions, then again during changes in body temperature and blood pressure, to test robustness. We will measure lag times and lag-time variability in all cases. Additionally, we will test our proprietary technology for preventing tissue encapsulation, which is one of the principle challenges facing efforts to implant sensors chronically.